WO2004096813A1 - Composes heterocycliques destines a etre utilises dans le traitement d'infections virales - Google Patents
Composes heterocycliques destines a etre utilises dans le traitement d'infections virales Download PDFInfo
- Publication number
- WO2004096813A1 WO2004096813A1 PCT/GB2004/001687 GB2004001687W WO2004096813A1 WO 2004096813 A1 WO2004096813 A1 WO 2004096813A1 GB 2004001687 W GB2004001687 W GB 2004001687W WO 2004096813 A1 WO2004096813 A1 WO 2004096813A1
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- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- decyl
- furo
- compound according
- alkenyl
- Prior art date
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- 208000036142 Viral infection Diseases 0.000 title claims abstract description 24
- 230000009385 viral infection Effects 0.000 title claims abstract description 23
- 238000011282 treatment Methods 0.000 title claims abstract description 19
- 150000002391 heterocyclic compounds Chemical class 0.000 title description 2
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 74
- 150000001875 compounds Chemical class 0.000 claims abstract description 63
- 125000003118 aryl group Chemical group 0.000 claims abstract description 43
- 125000003342 alkenyl group Chemical group 0.000 claims abstract description 32
- 125000000304 alkynyl group Chemical group 0.000 claims abstract description 26
- 241000701022 Cytomegalovirus Species 0.000 claims abstract description 15
- 229910052760 oxygen Inorganic materials 0.000 claims description 21
- 125000006413 ring segment Chemical group 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 17
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 claims description 17
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 16
- 229910052717 sulfur Inorganic materials 0.000 claims description 16
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 claims description 14
- 229910052757 nitrogen Inorganic materials 0.000 claims description 13
- 238000011321 prophylaxis Methods 0.000 claims description 11
- 125000005842 heteroatom Chemical group 0.000 claims description 9
- 239000003814 drug Substances 0.000 claims description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims description 8
- 125000003545 alkoxy group Chemical group 0.000 claims description 7
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 7
- 125000004104 aryloxy group Chemical group 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 6
- 239000002777 nucleoside Substances 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 125000004429 atom Chemical group 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229940127073 nucleoside analogue Drugs 0.000 claims description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims description 4
- 239000000651 prodrug Substances 0.000 claims description 4
- 229940002612 prodrug Drugs 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 125000006704 (C5-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000003282 alkyl amino group Chemical group 0.000 claims description 3
- 150000001356 alkyl thiols Chemical group 0.000 claims description 3
- 150000001504 aryl thiols Chemical group 0.000 claims description 3
- 125000004663 dialkyl amino group Chemical group 0.000 claims description 3
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims description 2
- 229910019142 PO4 Inorganic materials 0.000 claims description 2
- 150000001345 alkine derivatives Chemical group 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000001177 diphosphate Substances 0.000 claims description 2
- XPPKVPWEQAFLFU-UHFFFAOYSA-J diphosphate(4-) Chemical compound [O-]P([O-])(=O)OP([O-])([O-])=O XPPKVPWEQAFLFU-UHFFFAOYSA-J 0.000 claims description 2
- 235000011180 diphosphates Nutrition 0.000 claims description 2
- XQRLCLUYWUNEEH-UHFFFAOYSA-L diphosphonate(2-) Chemical compound [O-]P(=O)OP([O-])=O XQRLCLUYWUNEEH-UHFFFAOYSA-L 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 239000010452 phosphate Substances 0.000 claims description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 2
- 235000021317 phosphate Nutrition 0.000 claims description 2
- UEZVMMHDMIWARA-UHFFFAOYSA-M phosphonate Chemical compound [O-]P(=O)=O UEZVMMHDMIWARA-UHFFFAOYSA-M 0.000 claims description 2
- 150000003573 thiols Chemical group 0.000 claims description 2
- 239000001226 triphosphate Substances 0.000 claims description 2
- 235000011178 triphosphate Nutrition 0.000 claims description 2
- UNXRWKVEANCORM-UHFFFAOYSA-N triphosphoric acid Chemical compound OP(O)(=O)OP(O)(=O)OP(O)(O)=O UNXRWKVEANCORM-UHFFFAOYSA-N 0.000 claims description 2
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims 2
- 125000006651 (C3-C20) cycloalkyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- 125000001424 substituent group Chemical group 0.000 abstract description 11
- -1 6-substituted-3-substituted-3H-furo[2,3-d]pyrimidin-2-one Chemical class 0.000 abstract description 5
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 85
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 78
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 66
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 47
- 239000007787 solid Substances 0.000 description 46
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 34
- 239000002904 solvent Substances 0.000 description 33
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 32
- 238000005160 1H NMR spectroscopy Methods 0.000 description 32
- 238000003756 stirring Methods 0.000 description 29
- 239000000243 solution Substances 0.000 description 27
- 239000000203 mixture Substances 0.000 description 23
- 239000000725 suspension Substances 0.000 description 20
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 18
- 238000003818 flash chromatography Methods 0.000 description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 17
- 239000000047 product Substances 0.000 description 16
- 239000003480 eluent Substances 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 15
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 14
- 238000006243 chemical reaction Methods 0.000 description 13
- 238000000524 positive electrospray ionisation mass spectrometry Methods 0.000 description 13
- 239000011734 sodium Substances 0.000 description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 10
- 239000012267 brine Substances 0.000 description 9
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 9
- 125000002877 alkyl aryl group Chemical group 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000002027 dichloromethane extract Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000001931 aliphatic group Chemical group 0.000 description 7
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 230000000840 anti-viral effect Effects 0.000 description 6
- 238000000921 elemental analysis Methods 0.000 description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 6
- 238000009472 formulation Methods 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 5
- 241000701024 Human betaherpesvirus 5 Species 0.000 description 5
- 239000004480 active ingredient Substances 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 235000019198 oils Nutrition 0.000 description 5
- 238000006366 phosphorylation reaction Methods 0.000 description 5
- KSNXJLQDQOIRIP-UHFFFAOYSA-N 5-iodouracil Chemical compound IC1=CNC(=O)NC1=O KSNXJLQDQOIRIP-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 150000001408 amides Chemical class 0.000 description 4
- 239000007900 aqueous suspension Substances 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- GBRBMTNGQBKBQE-UHFFFAOYSA-L copper;diiodide Chemical compound I[Cu]I GBRBMTNGQBKBQE-UHFFFAOYSA-L 0.000 description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 4
- 208000015181 infectious disease Diseases 0.000 description 4
- 238000007912 intraperitoneal administration Methods 0.000 description 4
- 150000003833 nucleoside derivatives Chemical class 0.000 description 4
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000026731 phosphorylation Effects 0.000 description 4
- 238000000746 purification Methods 0.000 description 4
- 238000004809 thin layer chromatography Methods 0.000 description 4
- BLXSFCHWMBESKV-UHFFFAOYSA-N 1-iodopentane Chemical compound CCCCCI BLXSFCHWMBESKV-UHFFFAOYSA-N 0.000 description 3
- 241000701085 Human alphaherpesvirus 3 Species 0.000 description 3
- 239000012359 Methanesulfonyl chloride Substances 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- BRTFVKHPEHKBQF-UHFFFAOYSA-N bromocyclopentane Chemical compound BrC1CCCC1 BRTFVKHPEHKBQF-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- UQPUONNXJVWHRM-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 UQPUONNXJVWHRM-UHFFFAOYSA-N 0.000 description 3
- 239000011369 resultant mixture Substances 0.000 description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 238000001665 trituration Methods 0.000 description 3
- BHBJBGLJSNOWDS-UHFFFAOYSA-N (3-methylcyclopentyl) methanesulfonate Chemical compound CC1CCC(OS(C)(=O)=O)C1 BHBJBGLJSNOWDS-UHFFFAOYSA-N 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 2
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- YUIHSLYOPKDRCJ-UHFFFAOYSA-N 2-[(2-methylpropan-2-yl)oxy]oxolane Chemical compound CC(C)(C)OC1CCCO1 YUIHSLYOPKDRCJ-UHFFFAOYSA-N 0.000 description 2
- IZHVBANLECCAGF-UHFFFAOYSA-N 2-hydroxy-3-(octadecanoyloxy)propyl octadecanoate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCCCCCCCCCCC IZHVBANLECCAGF-UHFFFAOYSA-N 0.000 description 2
- VTOQFOCYBTVOJZ-UHFFFAOYSA-N 3-bromopentane Chemical compound CCC(Br)CC VTOQFOCYBTVOJZ-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- PKMUHQIDVVOXHQ-HXUWFJFHSA-N C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O Chemical compound C[C@H](C1=CC(C2=CC=C(CNC3CCCC3)S2)=CC=C1)NC(C1=C(C)C=CC(NC2CNC2)=C1)=O PKMUHQIDVVOXHQ-HXUWFJFHSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 239000012298 atmosphere Substances 0.000 description 2
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 2
- 229940073608 benzyl chloride Drugs 0.000 description 2
- 125000002619 bicyclic group Chemical group 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- KMGBZBJJOKUPIA-UHFFFAOYSA-N butyl iodide Chemical compound CCCCI KMGBZBJJOKUPIA-UHFFFAOYSA-N 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 229940126179 compound 72 Drugs 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- LSXDOTMGLUJQCM-UHFFFAOYSA-M copper(i) iodide Chemical compound I[Cu] LSXDOTMGLUJQCM-UHFFFAOYSA-M 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 125000000392 cycloalkenyl group Chemical group 0.000 description 2
- 210000002950 fibroblast Anatomy 0.000 description 2
- 239000007903 gelatin capsule Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 239000003701 inert diluent Substances 0.000 description 2
- 238000007918 intramuscular administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229940098779 methanesulfonic acid Drugs 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 125000002950 monocyclic group Chemical group 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- KHXQGLSTCGSGLW-UHFFFAOYSA-N oxolan-3-yl methanesulfonate Chemical compound CS(=O)(=O)OC1CCOC1 KHXQGLSTCGSGLW-UHFFFAOYSA-N 0.000 description 2
- 230000003389 potentiating effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
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- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
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- 231100000027 toxicology Toxicity 0.000 description 2
- ABJSOROVZZKJGI-OCYUSGCXSA-N (1r,2r,4r)-2-(4-bromophenyl)-n-[(4-chlorophenyl)-(2-fluoropyridin-4-yl)methyl]-4-morpholin-4-ylcyclohexane-1-carboxamide Chemical compound C1=NC(F)=CC(C(NC(=O)[C@H]2[C@@H](C[C@@H](CC2)N2CCOCC2)C=2C=CC(Br)=CC=2)C=2C=CC(Cl)=CC=2)=C1 ABJSOROVZZKJGI-OCYUSGCXSA-N 0.000 description 1
- GCTFTMWXZFLTRR-GFCCVEGCSA-N (2r)-2-amino-n-[3-(difluoromethoxy)-4-(1,3-oxazol-5-yl)phenyl]-4-methylpentanamide Chemical compound FC(F)OC1=CC(NC(=O)[C@H](N)CC(C)C)=CC=C1C1=CN=CO1 GCTFTMWXZFLTRR-GFCCVEGCSA-N 0.000 description 1
- FNHHVPPSBFQMEL-KQHDFZBMSA-N (3S)-5-N-[(1S,5R)-3-hydroxy-6-bicyclo[3.1.0]hexanyl]-7-N,3-dimethyl-3-phenyl-2H-1-benzofuran-5,7-dicarboxamide Chemical compound CNC(=O)c1cc(cc2c1OC[C@@]2(C)c1ccccc1)C(=O)NC1[C@H]2CC(O)C[C@@H]12 FNHHVPPSBFQMEL-KQHDFZBMSA-N 0.000 description 1
- MPDDTAJMJCESGV-CTUHWIOQSA-M (3r,5r)-7-[2-(4-fluorophenyl)-5-[methyl-[(1r)-1-phenylethyl]carbamoyl]-4-propan-2-ylpyrazol-3-yl]-3,5-dihydroxyheptanoate Chemical compound C1([C@@H](C)N(C)C(=O)C2=NN(C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C2C(C)C)C=2C=CC(F)=CC=2)=CC=CC=C1 MPDDTAJMJCESGV-CTUHWIOQSA-M 0.000 description 1
- OMBVEVHRIQULKW-DNQXCXABSA-M (3r,5r)-7-[3-(4-fluorophenyl)-8-oxo-7-phenyl-1-propan-2-yl-5,6-dihydro-4h-pyrrolo[2,3-c]azepin-2-yl]-3,5-dihydroxyheptanoate Chemical compound O=C1C=2N(C(C)C)C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)=C(C=3C=CC(F)=CC=3)C=2CCCN1C1=CC=CC=C1 OMBVEVHRIQULKW-DNQXCXABSA-M 0.000 description 1
- LFRDGHVRPSURMV-YFKPBYRVSA-N (4s)-4,5-dihydroxypentanal Chemical compound OC[C@@H](O)CCC=O LFRDGHVRPSURMV-YFKPBYRVSA-N 0.000 description 1
- 125000006376 (C3-C10) cycloalkyl group Chemical group 0.000 description 1
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 description 1
- DJMOXMNDXFFONV-UHFFFAOYSA-N 1,3-dimethyl-7-[2-(n-methylanilino)ethyl]purine-2,6-dione Chemical compound C1=NC=2N(C)C(=O)N(C)C(=O)C=2N1CCN(C)C1=CC=CC=C1 DJMOXMNDXFFONV-UHFFFAOYSA-N 0.000 description 1
- DMHZDOTYAVHSEH-UHFFFAOYSA-N 1-(chloromethyl)-4-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1 DMHZDOTYAVHSEH-UHFFFAOYSA-N 0.000 description 1
- KQZLRWGGWXJPOS-NLFPWZOASA-N 1-[(1R)-1-(2,4-dichlorophenyl)ethyl]-6-[(4S,5R)-4-[(2S)-2-(hydroxymethyl)pyrrolidin-1-yl]-5-methylcyclohexen-1-yl]pyrazolo[3,4-b]pyrazine-3-carbonitrile Chemical compound ClC1=C(C=CC(=C1)Cl)[C@@H](C)N1N=C(C=2C1=NC(=CN=2)C1=CC[C@@H]([C@@H](C1)C)N1[C@@H](CCC1)CO)C#N KQZLRWGGWXJPOS-NLFPWZOASA-N 0.000 description 1
- CGHIBGNXEGJPQZ-UHFFFAOYSA-N 1-hexyne Chemical compound CCCCC#C CGHIBGNXEGJPQZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
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- 239000001488 sodium phosphate Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
- C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
- C07D491/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/20—Antivirals for DNA viruses
- A61P31/22—Antivirals for DNA viruses for herpes viruses
Definitions
- the present invention relates to a chemical compound and to its therapeutic use in the prophylaxis and treatment of viral infection for example human herpes viruses, particularly and human cytomegalovirus (HCMV).
- Cytomegalovirus is the aetiological agent in CMV retinitis and other viral infections, which can cause considerable human illness and suffering.
- nucleoside analogues of the structural types 1 and 2 exhibit a potent and selective antiviral effect (McGuigan et al J. Med. Chem. 1999, 42, 4479-84 and J. Med. Chem. 2000, 43, 4993-97):
- the compounds exclusively inhibit Varicella zoster virus (VZV) in a VZV - thymidine-kinase dependent fashion, functioning in a classical nucleoside analogue manner, of obligate intracellular nucleoside kinase-mediated activation (Balzarini et al, Mol. Pharmacol. 61, 249-254, 2002).
- dideoxynucleoside analogues of 1 have a pronounced but quite distinct activity against another member of the herpes family, namely human cytomegalovirus HCMV.
- the optimal structure of these agents was identified as 3 and is described in WO 01/85749.
- R 1 and R 4 are independently selected from alkyl, aryl, alkenyl and alkynyl;
- Z is selected from O, NH, S, Se, NR 5 and (CH 2 ) n where n is 1 to 10, and CT 2 where T may be the same or different and is selected from hydrogen, alkyl and halogens, and
- R 5 is alkyl, alkenyl or aryl;
- Y is selected from N, CH and CR where R is alkyl, alkenyl, alkynyl or aryl;
- Q is selected from O, S, NH, N-alkyl, CH 2 , CHalkyl and C(alkyl) 2 ;
- U is selected from N and CR 2 where R 2 is selected from hydrogen, alkyl, halogens, amino, alkylamino, dialkylamino, nitro, cyano, alkoxy, aryloxy, thiol, alkylthiol, arylthiol and aryl;
- V is selected from N and CR where R is selected from hydrogen, alkyl, halogens, alkyloxy, aryloxy and aryl;
- X is selected from N, CH and CR 7 , where R 7 is selected from alkyl, alkenyl, alkynyl and aryl;
- R is alkyl, alkenyl, alkynyl or aryl, except that when Y is N, U is CR and V is CR , R is not an alkyl or alkenyl group substituted at the fourth atom of the chain of said alkyl or alkenyl group, counted along the shortest route away from the ring moiety including any hetero atom present in said chain, by a member selected from OH, phosphate, diphosphate, triphosphate, phosphonate, diphosphonate, triphosphonate and pharmacologically acceptable salts, derivatives and prodrugs thereof;
- the dideoxysugar in prior art compounds known from WO 01/85749 can be replaced by an alkyl, alkenyl, alkynyl or aryl moiety that does not require phosphorylation for biological activity and hence does not require the hydroxy or any groups on the, for example, alkyl C 4 atom deemed necessary for phosphorylation.
- neither R 4 nor R 8 contains any suitable hydroxy group that may be subject to biological phosphorylation.
- R 4 nor R 8 is a ribose, deoxyribase, dideoxyribose, dideoxydidehydribose sugar or similar sugar group or close analogue.
- Compounds having a double bond between X and the ring atom to which Q is attached are isomers of compounds having a single bond between X and the ring atom to which Q is attached.
- Compounds having a double bond between X and the ring atom to which Q is attached are entirely non-nucleosidic in nature. Examples of these two isomers are, for instance, structures 4 and 5:
- Varying the composition of R , R and R of formula (I) determines the biological activity of the compounds.
- Z is O or NH.
- Z is N-alkyl, suitably the alkyl is to C 5 alkyl.
- Y is N.
- Q is CH 2 , S or O. More preferably Q is O.
- Q is N-alkyl, suitably the alkyl is Ci to C 5 alkyl.
- Q is CHalkyl or C(alkyl) 2 , suitably the alkyl is d to C 5 alkyl.
- each of U and V is CH.
- X and Y are preferably both N.
- Z is preferably O.
- Q is preferably O.
- Q and Z are independently preferably selected from O, S and NH, more preferably Q and Z are O.
- alkyl includes cycloalkyl, alkyl substituted with cycloalkyl, alkyl containing within the alkyl chain 1, 2, 3 or 4 heteroatoms selected independently from O, S and N, substituted alkyl and branched alkyl;
- alkenyl includes cycloalkenyl, alkyl substituted with cycloalkenyl, alkenyl containing within the alkenyl chain 1, 2, 3 or 4 heteroatoms selected independently from O, S and N for example tetrahydrofuran (THF), substituted alkenyl and branched alkenyl;
- THF tetrahydrofuran
- alkynyl includes cycloalkynyl, alkyl substituted with cycloalkynyl, alkynyl containing within the alkynyl chain 1, 2, 3 or 4 heteroatoms selected independently from O, S and N, substituted alkynyl and branched alkynyl; and
- aryl includes monocyclic and bicyclic fused 5, 6 and 7 membered aromatic rings, aryl containing 1, 2, 3 or 4 heteroatoms selected independently from O, S and N, alkylaryl for example benzyl, and substituted aryl and substituted alkylaryl for example substituted benzyl.
- alkylaryl for example benzyl
- substituted aryl and substituted alkylaryl for example substituted benzyl.
- the nature, position and number of any substituents and unsaturation present in any alkyl, alkenyl, alkynyl and aryl group may be varied.
- alkyl, alkenyl, alkynyl and aryl, including alkylaryl, groups include OH, halogens, amino, CN, COOH, CO 2 alkyl(d to C 5 ), CONH 2 , CONHalkyl(C ⁇ to C 5 ), O-alkyl(C ⁇ to C 5 ), SH, S-alkyKQ to C 5 ) and NO 2 , and aryl(5 to 10 ring atoms), and with respect to aryl and alkylaryl groups include alkyl (d to C 5 ), alkenyl (C 2 to Cs) and alkynyl (C 2 to C 5 ), wherein any of said alkyl, alkenyl, alkynyl and aryl moieties are each optionally substituted.
- Substituents on the said alkyl, alkenyl and alkynyl moieties which are preferably straight chain, can be selected from the group comprising OH, halogens, amino, CN, SH and NO 2 , and is preferably a halogen, more preferably chlorine.
- the said alkyl, alkenyl or alkynyl moiety is C 2 to C 5 , the substituent is preferably at the terminus position.
- Substituents on the said aryl moiety can be selected from the group comprising OH, halogens, amino, CN, NO 2 , and Ci to Cio alkyl, which Ci to C 10 alkyl moiety is optionally substituted with a member selected from the group comprising OH, halogens, amino, CN, SH, NO 2 .
- the said aryl moiety can comprise aryl or heteroaryl groups. Any ring heteroatoms may vary in position or number. Suitably 1, 2, 3 or 4 heteroring atoms may be present, preferably selected, independently, from O, N and S.
- the said aryl moiety can comprise one, or two fused, 5, 6 or 7 membered rings.
- R 1 is selected from C 3-2 oalkyl, C 3-2 ocycloalkyl, C 2-2 oalkenyl, C -2 oalkynyl, C 5-14 aryl and C oalkylCs- ⁇ aryl, more preferably C 3 . 1 alkyl, C 3 . 14 alkenyl, C -14 alkynyl, more preferably C 6-1 alkyl, C 6-14 alkenyl, C 6-14 alkynyl, even more preferably C 8-1 oalkyl, C 8-1 o alkenyl and C 8-1 oalkynyl.
- R 1 is C 4-14 alkyl, C 4-14 alkenyl or C 4- ⁇ 4 alkynyl, more preferably C 4-12 alkyl, C 4- 12 alkenyl or C 4-12 alkynyl, even more preferably C 6-1 oalkyl, C 6-10 alkenyl or C 6-1 oalkynyl, even more preferably C 8-1 oalkyl, C 8-10 alkenyl or C 8-1 oalkynyl.
- R 1 is preferably C 6-12 alkyl, C 6-12 alkenyl or C 6-12 alkynyl. Where there is a double bond between X and the ring atom to which Q is attached, R 1 is preferably C 4- ⁇ 2 alkyl, C 4-12 alkenyl or C 4 - ⁇ 2 alkynyl.
- R 1 is an alkyl group.
- R 1 is a straight chain alkyl group.
- R 1 is an unsubstituted alkyl group.
- R 1 is a saturated alkyl group.
- R 1 is a C 7 to C 13 alkyl group. More preferably R 1 is a C 8 to C 12 alkyl group, even more preferably a C to Cn alkyl group. Particularly preferred is R 1 being a C or C 10 alkyl group.
- R 1 is a straight chain alkyl group
- a preferred position for substitution is the terminus position.
- any substituent in R 1 is non-polar, more suitably any such substituent is additionally hydrophobic.
- Preferred substituents on R 1 include halogen and O-alkyl(Ci to C 5 ). Particularly preferred is O-alkyl with C 4 , optionally terminally substituted with a halogen, preferably chlorine.
- R 1 is a cycloalkyl group, it suitably comprises 5 to 12 ring carbon atoms arranged in one or two adjoining rings.
- R 1 is selected from the group comprising nC 4 H , nC 6 H 13 , nC 7 H ⁇ 5 and nC 10 H 21 .
- R 1 is nC 10 H 2 ⁇ .
- R 4 and R 8 are selected from C 1-12 alkyl, C 2-12 alkenyl, C 2- ⁇ 2 alkynyl, C 3 _ 12 cycloalkyl, C 1-6 alkyl substituted with C 3-10 cycloalkyl, Cs- ⁇ aryl and C 1-5 alkylC 5-14 aryl.
- R and R are selected from C ⁇ oalkyl C 2-10 alkenyl, C 2-10 alkynyl, Cialkyl substituted with C 5-6 cycloalkyl and Qalkyl substituted with C 5- aryl.
- R 4 and R 8 are selected from C 1-6 alkyl, C 2- alkenyl, Qalkyl substituted with Cs -6 cycloalkyl and benzyl and substituted benzyl.
- each of R 4 and R 8 are selected from the group comprising cycloC 5 H , CH(Et) 2 , nCsHn, 2-THF, CH 2 cycloC 6 H ⁇ , 3-THF, cycloC 6 H ⁇ , C 3 H 7 , nC 4 H 9 , PhCH 2 , TolCH 2 , ⁇ MeOPhCH 2 , CH 2 cycloC 5 H 9 , Me and nC 3 H 7 .
- R 1 and R 8 are, respectively, nC 7 H 15 and cycloC 5 H , nC 7 H 15 and CH(Et) 2 , nC 10 H 2 ⁇ and 3-THF, nC 10 H 21 and cycloC 6 H ⁇ , nC 10 H 21 and C 3 H 7 , nC 10 H 2 ⁇ and CH 2 cycloC 5 H , nC 6 H 13 and Me, nCeH ⁇ 3 and nC 3 H , and nC 6 H 13 and PhCH 2 .
- a particularly preferred combination is R 1 being nC 10 H 21 and R 8 being CH 2 cycloCsH 9 .
- R 1 and R 4 are, respectively, nC 4 H 9 and cycloCsH , nC 7 H 15 and cycloC 5 H 9 , nC 7 H 5 and CH(Et) 2 , nC 7 H 15 and nC 5 H n , nC 10 H 21 and CH(Et) 2 , nC 10 H 2 ⁇ and cycloC 6 H ll5 nC 10 H 21 and nC 3 H , nC 10 H 2 ⁇ and 11C 4 H 9 , nC 10 H 21 and PhCH 2 , nC ⁇ oH 21 and CH 2 cycloC 6 H ⁇ , nC ⁇ oH 2 ⁇ and TolCH 2 , nC ⁇ 0 H 21 and pMeOPhCH 2 , nC 6 H ⁇ and Me, nC 6 H 13 and nC 4 H 9 , and nC 6 H 13 and
- R 1 being nC 10 H 21 with R 4 being any of nC 3 H 7 , nQHc*, PhCH 2 , CH 2 cycloC 6 Hn, tolCH 2 , and pMeOPhCH 2 .
- R 2 is selected from the group comprising H, Ci to C 10 alkyl, C 3 to C 10 cycloalkyl, Ci to C 10 alkylamino, d to Cio dialkylamino, Ci to C 10 alkyloxy, C 6 to Cio aryloxy, to Cio alkylthiol, C 6 to Cio arylthiol and C 6 to Cio aryl.
- R 3 is selected from the group comprising H, Ci to Cio alkyl, C 3 to Cio cycloalkyl, Ci to Cio alkyloxy, C 6 to Cio aryloxy and C to Cio aryl.
- each of R 2 and R 3 is a small alkyl i.e. a to C 2 alkyl group or H. More preferably each of R 2 and R 3 is H.
- halogen is taken to include any of F, CI, Br and I.
- alkyl is C ⁇ -6 alkyl
- alkenyl is C 2-6 alkenyl
- alkynyl is C 2 .
- aryl is Cs-w ryl
- alkylaryl is C ⁇ -6 alkylC 5 - ⁇ aryl.
- R 1 , R 4 or R 8 is an aryl group
- the group includes alkylaryl groups.
- R 1 , R 4 and R 8 are Cs- ⁇ aryl groups or C ⁇ - 4 alkylC 5- i 4 aryl groups.
- Particularly preferred groups are benzyl and subtituted benzyl such as toluene (tol)CH 2 , and pMeOPhCH 2 .
- Preferred substituents include alkyl (C ⁇ -6 ), alkoxy (C ⁇ -6 ) and halogen (F, CI, Br and I).
- the preferred substitution positions for phenyl and benzyl is para.
- Preferred aryl groups are C 6 .
- R 1 is alkyl, preferably R 1 is C 6- ⁇ 2 alkyl; when R 1 is alkynyl, preferably R 1 is C 8 or above alkynyl, more preferably C 8- 2 oalkynyl, even more preferably C 8- ⁇ alkynyl; even more preferably C 8 _ ⁇ 2 alkynyl; even more preferably C 8- ⁇ oalkynyl; when R 1 is aryl, preferably R 1 is a monocyclic or bicyclic fused 5, 6 or 7 membered ring, an aryl group containing 1, 2, 3 or 4 heteroatoms selected independently from O, S and N, alkylaryl for example benzyl, or substituted aryl or substituted alkylaryl for example substituted benzyl such as pMeOPhCH 2 , more preferably a C 5 _i aryl group or a aryl group,
- a compound according to the present invention for use in a method of treatment, suitably in the prophylaxis or treatment of a viral infection, preferably a cytomegalovirus infection; a method of prophylaxis or treatment of a viral infection, preferably a cytomegalovirus infection; and use of a compound of the present invention in the manufacture of a medicament for use in the prophylaxis or treatment of a viral infection, particularly an infection with cytomegalovirus.
- a method for preparing compounds having Formula I above wherein a 5-halo nucleoside analogue is contacted with a terminal alkyne in the presence of a catalyst.
- 5-alkynyl nucleoside can be cyclised in the presence of a catalyst.
- the catalyst is a copper catalyst.
- terminal acetylenes are coupled to 5-iodouracil under Pd catalysed conditions to give intermedaite 5-alkynyl compounds that may either be isolated or used in situ. These are cyclised under Cu catalysis to give bicyclic furano pyrimidines that are key synthons. These are alkylated to give mixtures of O and N alkyl products that can be readily separated.
- the method of separation may include chromatography, precipitation, and crystallisation.
- the ratios of these products will vary, and need not be 1 :1.
- Compounds embodying the present invention can show anti-viral activity.
- compounds embodying the present invention can show antiviral activity against for example cytomegalovirus.
- a compound according to the present invention for use in a method of treatment, suitably in the prophylaxis or treatment of a viral infection, preferably a cytomegalovirus viral infection.
- a method of prophylaxis or treatment of viral infection comprising administration to a patient in need of such treatment an effective dose of a compound according to the present invention.
- a compound of the present invention in the manufacture of a medicament for use in the prophylaxis or treatment of a viral infection, particularly an infection with cytomegalovirus.
- a pharmaceutical composition comprising a compound of the present invention in combination with a pharmaceutially acceptable excipient.
- a method of preparing a pharmaceutical composition comprising the step of combining a compound of the present invention with a pharmaceutically acceptable excipient.
- the high lipophilicity of the present compounds may lead to improved in vivo dosing, tissue distribution and pharmacokinetics.
- no visible in vivo toxicity was noted, indicating a promising toxicology profile. Histology also revealed no detectable toxicity against brain, thymus, liver, lungs, kidney, breast, testi, ovum and spleen tissue.
- the compounds embodying the present invention can be sufficiently lipophilic to warrant their formulation and use as non-p.o dosage forms including topical, transdermal and ocular formulations.
- the latter may be of particular value versus HCMV retinitis, common in persons co-infected with HIV.
- the agents would therein have significant dosing, tissue localisation and toxicology advantage over current agents.
- the medicaments employed in the present invention can be administered by oral (p.o.) or parenteral (i.p.) routes, including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
- oral p.o.
- parenteral i.p.
- routes including intravenous, intramuscular, intraperitoneal, subcutaneous, transdermal, airway (aerosol), rectal, vaginal and topical (including buccal and sublingual) administration.
- the compound of the invention will generally be provided in the form of tablets or capsules, as a powder or granules, or as an aqueous solution or suspension.
- Tablets for oral use may include the active ingredient mixed with pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavouring agents, colouring agents and preservatives.
- suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
- Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc.
- the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
- Capsules for oral use include hard gelatin capsules in which the active ingredient is mixed with a solid diluent, and soft gelatin capsules wherein the active ingredient is mixed with water or an oil such as peanut oil, liquid paraffin or olive oil.
- Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate.
- Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
- the compounds of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
- Suitable aqueous vehicles include ringer's solution and isotonic sodium chloride.
- Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecitliin.
- Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
- the compounds of the invention may also be presented as liposome formulations.
- a suitable dose will be in the range of 0.1 to 300 mg per kilogram body weight of the recipient per day, preferably in the range of 1 to 25 mg per kilogram body weight per day and most preferably in the range 5 to 10 mg per kilogram body weight per day.
- the desired dose is preferably presented as two, three, four, five or six or more sub-doses administered at appropriate intervals throughout the day. These sub-doses may be administered in unit dosage forms, for example, containing 10 to 1500 mg, preferably 20 to 1000 mg, and most preferably 50 to 700 mg of active ingredient per unit dosage form.
- Splitting pattern is designated as follows: s, singlet; app d, apparent doublet; d, doublet; dd, double doublet; t, triplet; q, quartet; quin, quintet; sex, sextet; sept, septet; m, multiplet; and br, broad. Elemental analyses were carried out in the Microanalytical Laboratories of the School of Pharmacy, University of London.
- 6-Decyl-2,3-dihydroft ⁇ ro[2,3- ⁇ pyrimidin-2-one 26 200 mg, 0.72 mmol
- potassium carbonate 199 mg, 1.44 mmol, 2 equiv.
- 1-iodopentane 36 0.2 mL, 2 equiv.
- the solvent was removed in vacuo al 80 °C, with subsequent additions and removals of toluene (2 mL) to eliminate DMF traces.
- the crude residue was purified by flash column chromatography to yield 37 (88 mg, 35 %) as a cream solid.
- Tlie title compound 72 (157 mg, 42 %) was also isolated from the reaction mixture as a white solid.
- 3-Hydroxytetrahydrofuran 57 (0.50 g, 0.46 mL, 5.5 mmol) and triethylamine (1 mL, 7 mmol, 1.3 equiv.) were dissolved in dry DCM (5 mL) and the solution cooled to 0 °C with stirring.
- Methanesulfonyl chloride 63 (0.55 mL, 7 mmol, 1.3 equiv.) was added slowly via syringe to the drilled solution. The solution was allowed to warm to RT, and the resultant suspension stirred at RT for 24 h. Dry DCM (20 mL) was then added to the suspension to re-form a solution.
- the solution was allowed to stir at RT for a further 36 h.
- the solvent was removed in vacuo and the residue dissolved in water.
- the aqueous solution was extracted with DCM.
- the DCM extracts were then washed with brine, and the brine washings extracted with fresh DCM.
- the combined organic layers were then dried over MgSO 4 .
- the solvent was removed under reduced pressure to yield 64 as a yellow viscous liquid (0.80 g, 96 %), which was used without further purification.
- Tetral ⁇ ydro-3-furan methanol 65 (0.50 g, 4.9 mmol) was dissolved in dry DCM (30 mL) and triethylamine (1.06 mL, 8.8 mmol, 1.8 equiv) was added to the solution via syringe under N 2 with stirring. The solution was cooled to 0 °C and metlianesulfonyl chloride 63 (0.68 mL, 8.8 mmol, 1.8 equiv) added dropwise via syringe. The resultant solution was allowed to warm to RT and stirred at RT for 36 h. The solvent was then removed in vacuo. The residue was dissolved in fresh DCM and water (25 mL) added to the solution.
- Tefrahydrofurfuryl alcohol 69 (0.50 g, 4.9 mmol) was dissolved in dry DCM (30 mL) and triethylamine (1.06 mL, 8.8 mmol, 1.8 equiv) was added to the solution via syringe under N 2 with stirring. The solution was cooled to 0 °C and methanesulfonyl chloride 63 (0.68 mL, 8.8 mmol, 1.8 equiv) added dropwise via syringe to the cooled solution. The resultant solution was allowed to warm to RT and stirred at RT for 36 h. The solvent was then removed in vacuo.
- 3-Methylcyclopentanol 75 (0.5 g, 4.99 mmol) was dissolved in dry DCM (25 mL), and triethylamine (0.8 mL, 6.5 mmol, 1.3 equiv) added to the stirred solution under N 2 , which was then cooled to 0 °C.
- Methanesulfonyl chloride (0.5 mL, 6.5 mmol, 1.3 equiv) was added dropwise via syringe to the chilled solution, the resultant solution warmed to RT and allowed to react at RT with stirring for 36 h.
- the solvent was removed in vacuo, and the residue dissolved in water (50 mL), which was extracted with DCM (5 X 50 mL).
- the combined DCM extracts were washed with brine (which was back extracted with fresh DCM (25mL)), dried (MgSO 4 ), filtered and reduced under vacuum to yield a clear yellow oil (789 mg, 88 %).
- 6-Decyl-2,3-dihydrofuro[2,3- ⁇ pyrimidin-2-one 26 (0.50 g, 1.81 mmol) and potassium carbonate (0.50 g, 3.62 mmol, 2 equiv.) were suspended in dry DMF (6 mL), and 4- mefhoxybenzyl chloride (0.5 mL, 3.62 mmol, 2 equiv) added to the stirred solution via syringe under N 2 .
- the resultant mixture was heated with stirring to 120 °C overnight.
- 6-Decyl-2,3-dmydrofuro[2,3- ⁇ pyrimidin-2-one 26 (0.50 g, 1.81 mmol), potassium carbonate (0.50 g, 3.62 mmol, 2 equiv) were suspended in dry DMF (5 ml) and 4- methylbenzyl chloride (0.5 mL, 3.62 mmol, 2 equiv) added to the stirred suspension under N 2 via syringe. The resultant mixture was then heated at 100 °C overnight.
- 5-Iodouracil 23 (5.00 g, 21 mmol), teirakis(triphenylphosphine)palladium(0) (1.0 g, 0.87 mmol, 0.04 equiv), and copper iodide (0.80 g, 4.2 mmol, 0.2 equiv) were dissolved in dry DMF (50 mL) with stirring under N 2 .
- 6-Hexyl-2,3-dmydrofuro[2,3-f ] ⁇ yrimidin-2-one 38 (0.40 g, 1.82 mmol) and potassium carbonate (0.50 g, 3.64 mmol, 2 equiv) were suspended in dry DMF (5 mL) under N 2 and methyl iodide (0.23 mL, 3.64 mmol, 2 equiv) added via syringe to the stirred suspension, which was then heated to 80 °C ovemiglit. The solvents were removed in vacuo and the crude purified by flash column chromatography in a 0-5% MeOH/DCM solvent gradient to yield the title product 40 as a white solid in very low yield (25 mg, 6 %).
- 6-Hexyl-2,3-dmydrofuro[2,3-d]pyrimidin-2-one 38 (0.40 g, 1.82 mmol), potassium carbonate (0.50 g, 3.65 mmol, 2 equiv) and 1 -iodobutane (0.41 mL, 3.62 mmol, 2 equiv) were suspended in dry DMF (5 mL) under N 2 and heated to 80 °C with stirring overnight. The solvents were removed in vacuo and the crude purified by flash column chromatography in a 0-5% MeOH/DCM solvent gradient to yield the title product 42 as a white solid (180 mg, 36 %).
- 6-Hexyl-2,3-dmydrofuro[2,3-c j ⁇ yrimidin-2-one (44, 0.40 g, 1.82 mmol) and potassium carbonate (0.50 g, 3.64 mmol, 2 equiv) were added under N 2 to dry DMF (5 mL), and the resultant suspension charged with benzyl chloride 43 (0.42 mL, 3.64 mmol, 2 equiv), then heated to 80 °C overnight.
- the solvents were removed in vacuo and the crude purified by flash column chromatography in a 0-5% MeOH/DCM eluent gradient to yield 39 mg (44, 7 %) of the title compound as a white solid.
- R 1 , R 4 and R 8 are as defined with respect to formula I above.
- EC 50 / ⁇ m CMV- AD 169 is the drug concentration in ⁇ M required to reduce by 50% CMV strain AD 169 induced cytopathicity in human embryonic lung fibroblast (HEL) cells measured 7 days post infection compared to untreated control.
- EC 50 / ⁇ M CMV Davis is the drug concentration in ⁇ M required to reduce by 50% CMV strain Davis induced cytopathicity in human embryonic lung fibroblast (HEL) cells measured 7 days post infection compared to untreated control.
- CC 5 o/ ⁇ M is the compound concentration required to reduce the cell number by 50%.
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Abstract
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MXPA05010802A MXPA05010802A (es) | 2003-04-25 | 2004-04-21 | Compuestos heterociclicos para el uso en el tratamiento de infecciones virales. |
CA002523739A CA2523739A1 (fr) | 2003-04-25 | 2004-04-21 | Composes heterocycliques destines a etre utilises dans le traitement d'infections virales |
JP2006506149A JP2006524672A (ja) | 2003-04-25 | 2004-04-21 | ウイルス感染の治療において使用するための複素環式化合物 |
US10/551,569 US20070191373A1 (en) | 2003-04-25 | 2004-04-21 | Heterocyclic compounds for use in the treatment of viral infections |
AU2004234110A AU2004234110A1 (en) | 2003-04-25 | 2004-04-21 | Heterocyclic compounds for use in the treatment of viral infections |
EP04728594A EP1622913A1 (fr) | 2003-04-25 | 2004-04-21 | Composes heterocycliques destines a etre utilises dans le traitement d'infections virales |
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EP (1) | EP1622913A1 (fr) |
JP (1) | JP2006524672A (fr) |
AU (1) | AU2004234110A1 (fr) |
CA (1) | CA2523739A1 (fr) |
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Cited By (9)
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US6083923A (en) * | 1997-10-31 | 2000-07-04 | Isis Pharmaceuticals Inc. | Liposomal oligonucleotide compositions for modulating RAS gene expression |
WO2011086081A1 (fr) * | 2010-01-14 | 2011-07-21 | Sanofi-Aventis | Dérivés d'oxazolopyrimidine à substitution en 2,5 |
WO2011086079A1 (fr) * | 2010-01-14 | 2011-07-21 | Sanofi-Aventis | Dérivés d'acide carboxylique comprenant un noyau d'oxazolopyrimidine à substitution en 2,5 |
US8324239B2 (en) | 2010-04-21 | 2012-12-04 | Novartis Ag | Furopyridine compounds and uses thereof |
EP2583720A1 (fr) | 2008-07-15 | 2013-04-24 | Sanofi | Oxazolopyrimidines en tant qu'agonistes du récepteur Edg.1 |
US8551966B2 (en) | 2011-07-08 | 2013-10-08 | University College Cardiff Consultants Limited | Chemical compounds |
US8748436B2 (en) | 2010-01-13 | 2014-06-10 | Sanofi | Carboxylic acid derivatives having a 2,5,7-substituted oxazolopyrimidine ring |
US8785439B2 (en) | 2010-01-13 | 2014-07-22 | Sanofi | 2,5,7-substituted oxazolopyrimidine derivatives |
WO2021255089A1 (fr) | 2020-06-19 | 2021-12-23 | Bayer Aktiengesellschaft | 1,3,4-oxadiazole pyrimidines et 1,3,4-oxadiazole pyridines utilisées comme fongicides |
Families Citing this family (1)
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CN105189515B (zh) | 2013-03-14 | 2018-07-03 | 葛兰素史克知识产权第二有限公司 | 作为溴结构域抑制剂的呋喃并吡啶类 |
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WO2002083651A2 (fr) * | 2001-04-11 | 2002-10-24 | Queen's University At Kingston | Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques |
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2004
- 2004-04-21 EP EP04728594A patent/EP1622913A1/fr not_active Withdrawn
- 2004-04-21 WO PCT/GB2004/001687 patent/WO2004096813A1/fr active Application Filing
- 2004-04-21 US US10/551,569 patent/US20070191373A1/en not_active Abandoned
- 2004-04-21 AU AU2004234110A patent/AU2004234110A1/en not_active Abandoned
- 2004-04-21 MX MXPA05010802A patent/MXPA05010802A/es unknown
- 2004-04-21 JP JP2006506149A patent/JP2006524672A/ja not_active Withdrawn
- 2004-04-21 CA CA002523739A patent/CA2523739A1/fr not_active Abandoned
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WO2002083651A2 (fr) * | 2001-04-11 | 2002-10-24 | Queen's University At Kingston | Composes de pyrimidine en tant qu'agents anti-ictogeniques et/ou anti-epileptiques |
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Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6083923A (en) * | 1997-10-31 | 2000-07-04 | Isis Pharmaceuticals Inc. | Liposomal oligonucleotide compositions for modulating RAS gene expression |
EP2583720A1 (fr) | 2008-07-15 | 2013-04-24 | Sanofi | Oxazolopyrimidines en tant qu'agonistes du récepteur Edg.1 |
US8735387B2 (en) | 2008-07-15 | 2014-05-27 | Sanofi | Oxazolopyrimidines as Edg-1 receptor agonists |
US8785439B2 (en) | 2010-01-13 | 2014-07-22 | Sanofi | 2,5,7-substituted oxazolopyrimidine derivatives |
US8748436B2 (en) | 2010-01-13 | 2014-06-10 | Sanofi | Carboxylic acid derivatives having a 2,5,7-substituted oxazolopyrimidine ring |
US9040544B2 (en) | 2010-01-14 | 2015-05-26 | Sanofi | 2,5-substituted oxazolopyrimidine derivatives |
CN102834400A (zh) * | 2010-01-14 | 2012-12-19 | 赛诺菲 | 2,5-取代的*唑并嘧啶衍生物 |
CN102791717A (zh) * | 2010-01-14 | 2012-11-21 | 赛诺菲 | 具有2,5-取代的噁唑并嘧啶环的羧酸衍生物 |
WO2011086079A1 (fr) * | 2010-01-14 | 2011-07-21 | Sanofi-Aventis | Dérivés d'acide carboxylique comprenant un noyau d'oxazolopyrimidine à substitution en 2,5 |
US8846692B2 (en) | 2010-01-14 | 2014-09-30 | Sanofi | Carboxylic acid derivatives having a 2,5-substituted oxazolopyrimidine ring |
WO2011086081A1 (fr) * | 2010-01-14 | 2011-07-21 | Sanofi-Aventis | Dérivés d'oxazolopyrimidine à substitution en 2,5 |
CN102834400B (zh) * | 2010-01-14 | 2015-06-10 | 赛诺菲 | 2,5-取代的*唑并嘧啶衍生物 |
CN102791717B (zh) * | 2010-01-14 | 2016-03-30 | 赛诺菲 | 具有2,5-取代的噁唑并嘧啶环的羧酸衍生物 |
US8324239B2 (en) | 2010-04-21 | 2012-12-04 | Novartis Ag | Furopyridine compounds and uses thereof |
US8551966B2 (en) | 2011-07-08 | 2013-10-08 | University College Cardiff Consultants Limited | Chemical compounds |
WO2021255089A1 (fr) | 2020-06-19 | 2021-12-23 | Bayer Aktiengesellschaft | 1,3,4-oxadiazole pyrimidines et 1,3,4-oxadiazole pyridines utilisées comme fongicides |
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JP2006524672A (ja) | 2006-11-02 |
MXPA05010802A (es) | 2005-12-14 |
US20070191373A1 (en) | 2007-08-16 |
AU2004234110A1 (en) | 2004-11-11 |
CA2523739A1 (fr) | 2004-11-11 |
EP1622913A1 (fr) | 2006-02-08 |
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